4 YEAR PhD IN NEUROSCIENCE
Department of Neuroscience, Physiology & Pharmacology
Neuronal nicotinic acetylcholine receptors
Our research group uses a wide range of
molecular biological, cell biological, pharmacological and electrophysiological
techniques to investigate the structural and functional properties of neuronal
nicotinic acetylcholine receptors (nAChRs). One of our main experimental
approaches is to examine the properties of recombinant nAChRs expressed in
either cultured cell lines or Xenopus
oocytes. Nicotinic receptors are increasingly seen as important targets for
therapeutic drug discovery and in recent years our group has collaborated with
several pharmaceutical companies. We have also established a productive
collaboration with Dr Tom Sheppard’s group in the department of Chemistry at
UCL. This has resulted in the synthesis and pharmacological characterisation of
several novel compounds acting on nAChRs.
Allosteric modulation of neuronal nAChRs
This project will examine the pharmacological properties of allosteric modulators and allosteric agonists on neuronal nAChRs. Such compounds have attracted considerable interest from pharmaceutical companies as potential therapeutic tools for the treatment of a range of neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. Whereas conventional agonists such as acetylcholine activate nAChRs via an extracellular ‘orthosteric’ binding site, a variety of compounds have been identified that bind to nAChRs at distinct allosteric sites. Work from our lab has revealed that several pharmacologically interesting compounds, including positive allosteric modulators (PAMs) and allosteric agonists, interact with an intrasubunit transmembrane binding site. More recently we have obtained evidence that compounds with five distinct pharmacological effects interact with this transmembrane allosteric site. A research project is available that will use a range of molecular and pharmacological techniques to extend these studies and help to elucidate the mechanism of action of this diverse group of nAChR allosteric modulators.
Experimental techniques to be used during the rotation project
The project will involve a combination of molecular biological techniques and functional assays. Subunit cDNAs will be altered by site-directed mutagenesis and the influence of these mutations will be examined by techniques such as two-electrode voltage clamp electrophysiology in Xenopus oocytes and by fluorometric intracellular calcium assays in cultured cell lines.
Gill, J.K., Dhankher, P., Sheppard, T.D.,
Sher, E. and Millar, N.S. (2012)
A series of α7 nicotinic allosteric modulators with close chemical similarity but diverse pharmacological properties.
Molecular Pharmacology 81, 710-718.
Jindrichova, M., Gibb, A.J. and Millar, N.S. (2012)
Activation of α7 nicotinic receptors by orthosteric and allosteric agonists: influence on single-channel kinetics and conductance.
Molecular Pharmacology 82, 910-917.
Savolainen, M., Young, G.T., Zwart, R., Sher, E. and Millar, N.S. (2011)
Agonist activation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site.
Proceedings of the National Academy of Sciences USA 108, 5867-5872.
Young, G.T., Zwart,
R., Walker, A.S., Sher, E. and Millar, N. S. (2008)
Potentiation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site.
Proceedings of the National Academy of Sciences USA 105, 14686-14691.